The present invention relates generally to a novel antigen and to novel hybridoma cell lines, and more specifically to monoclonal cell lines producing monoclonal antibodies reactive with the novel antigen, which antigen can be found, inter alia, on human pancreatic cancer cells.
Cancer currently constitutes the second most common cause of death in the United States. Carcinomas of the pancreas are the eighth most prevalent form of cancer and fourth among the most common causes of cancer deaths in this country. The incidence of pancreatic cancer has been increasing steadily in the past twenty years in most industrialized countries, exhibiting the characteristics of a growing epidemiological problem.
The prognosis for pancreatic carcinoma is, at present, very poor, it displays the lowest five-year survival rate among all cancers. Such prognosis results primarily from delayed diagnosis, due in part to the fact that the early symptoms are shared with other more common abdominal ailments. The diagnosis of pancreatic cancer is often dependent on exploratory surgery, inevitably performed after the disease has advanced considerably.
Substantial efforts have been directed to developing tools useful for early diagnosis of pancreatic and other carcinomas. Nonetheless, a definitive diagnosis is often dependent on exploratory surgery which is inevitably performed after the disease has advanced past the point when early treatment may be effected. One promising method for early diagnosis of various forms of cancer is the identification of specific biochemical moieties, termed antigens present on the surface of cancerous cells. Antibodies which will specifically recognize and bind to the antigens present on the surfaces of cancer cells potentially provide powerful tools for the diagnosis and treatment of the particular malignancy. Tumor specific cell surface antigens have previously been identified for certain melanomas, lymphomas malignancies of the colon and reproductive tract.
There thus exists a great and long-felt need for a cell surface marker which is present on the surface of neoplastic cells, including those of the pancreas, and for antibodies which specifically recognize such a cell surface marker. Such markers and corresponding antibodies would be useful not only in the early detection of pancreatic and other cancers, but in their treatment as well. The present invention satisfies these needs and provides related advantages as well.
Secondly, the interaction of cells with the extracellular matrix is important for the formation, maintenance, and repair of tissues as well as other biological processes such as the metastasis of cancer cells. This cellular adhesion is mediated, in part, by a family of cell surface receptors called integrins (Hynes, (1987) Cell 48:549-554; Ruoslahti and Pierschbacher, (1987) Science 238:491-497; Buck and Horwitz, (1987) Ann. Rev. Cell Biol. 3:179-205). These receptors form a link between the extracellular matrix and the cytoskeleton and may transmit signals from the extracellular to the intracellular environment which affect cell behavior.
Cell adhesion is critical to many biological processes, including embryonal development, tissue repair, immune response, and malignant transformation. (Ekblom, P., et al. (1986) Ann. Rev. Cell. Biol. 2:27 47; Yamada, K. M. (1983) Ann. Rev. Biochem. 52:761-799; Edelman, G. M. (1983) Science 219:450-457.) Several laboratories have recently done biochemical characterization of adhesion receptors for extracellular matrix and plasma proteins such as fibronectin and vitronectin as well as leukocyte adhesion receptors. (Tamkun, J. W., et al. (1986) Cell 46:271-282; Damsky, C. H., et al. (1981) J. Cell. Biol. 89:173-184; Pytela, R., et al. (1985) Cell 40:191-198; Fitzgerald, L. A., et al. (1987) J. Biol. Chem. 262:3936-3939; Giancotti, F. G. (1985) Exp. Cell Res. 156:182-190; Springer, T. A. (1985) Nature 314:540-542.)
These adhesion receptor proteins have been shown to be structurally homologous to each other. (Charo, I. F. (1986) Proc. Nat'l Acad. Sci. USA 83:8351-8355; Suzuki, S. (1986) Proc. Nat'l Acad. Sci. USA 83:8416-8418; Kishimoto, T. K. (1987) Cell 48:681-690; Takada, Y. (1987) Nature 326:607-609.) These related molecules have now been organized into a protein superfamily, designated "/integrins", after the chicken fibronectin/laminin receptor. (Hynes, R. O. (1987) Cell 48:549-554.)
Integrins are heterodimers comprised of .alpha.- and .beta.-subunits that are noncovalently associated, transmembrane glycoproteins. At least 11 .alpha.-chains (Ruoslahti and Giancotti, (1989) Cancer Cells 1:119-126) and 6 .beta.-chains (Sheppard et al , (1990) J. Biol. Chem. 265:11502-11507) have been recognized in humans. Each .alpha.-subunit tends to associate with only one type of .beta.-subunit, but there are several exceptions to this rule (Hemler et al., (1989) J. Biol. Chem. 264:6529-6535; Sonnenberg et al., (1988) Nature 336:487-489; Kennel et al., (1989) J. Biol. Chem. 264:15515-15521; Cheresh et al., (1989) Cell 57:59-69; Holzmann et al., (1989) Cell 56:37-46; Freed et al., (1989) EMBO 8:2955-2965).
There thus has been a great and long-felt need for an understanding of cell surface markers, such as integrins or cell adhesion receptors, which are present on neoplastic cells, not only those of the pancreas, and for antibodies which specifically recognize such markers. To understand the marker at a molecular level would provide for a refinement in the early detection of cancers or other pathologies involving cell adhesion disorders, such as epithelial disorders, as well as in their treatment. The present invention satisfies these needs and provides additional advantages as well.